N-[2(o-iodophenoxy)ethyl]cyclopropylamine hydrochloride (LY121768), a potent and selective irreversible inhibitor of type a monoamine oxidase

The effects of N-2-(o-iodophenoxy)ethyl]cyclopropylamine hydrochloride (LY121768) on types A and B monoamine oxidase (MAO) assayed with radiocarbon-labeled serotonin and phenyl-ethylamine, respectively, were studied in vitro and in vivo. Type A MAO from rat brain was inhibited in vitro by LY121768 with an ic₅₀ of 4 × 10^?10 M, whereas 2500 times higher concentrations of LY121768 $\text{(}\text{ic}{}_{50}\text{= 1 × 10}{}^{\mathrm{?6}}\text{M}\text{)}$ were required to inhibit type B MAO. The inhibition of type A MAO increased with time of incubation of LY121768 with enzyme prior to substrate addition and persisted after dialysis, indicative of irreversible inhibition. The irreversible inactivation was prevented by harmaline, a reversible, competitive inhibitor of type A MAO, indicating a requirement for catalytic activity of MAO in the time-dependent inactivation by LY121768. In rats, LY121768 selectively inhibited type A MAO in brain and in liver at low doses. The inhibition of type A MAO persisted for several days after a single 10 mg/kg i.p. dose of LY121768 and was associated with a significant increase in brain dopamine, norepinephrine and epinephrine concentrations and a significant decrease in the concentration of the dopamine metabolites, homovanillic acid and 3.4-dihydroxyphenylacetic acid. The inactivation of type A MAO by LY121768 in vivo was prevented by co-administration of harmaline, indicating a similar mechanism for the in vivo inactivation as for the in vitro inactivation of MAO by LY121768. A reasonable inference from these data and from previous literature is that LY121768 acts as a “suicide substrate” for MAO and inactivates the enzyme by formation of a reactive intermediate which binds covalently to the enzyme. The presence of iodine in the LY121768 molecule not only confers high selectivity for type A MAO but offers a site for radionuclide introduction that might be a useful means of labeling type A MAO in vitro or in vivo for various purposes.